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1.
Int J Cancer ; 154(9): 1607-1615, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38196128

ABSTRACT

The relationships between the therapeutic effects of immune checkpoint inhibitors (ICIs) and the intestinal flora have attracted increasing attention. However, the effects of oral probiotics on the efficacies of ICIs used to treat non-small-cell lung cancer (NSCLC) remain unclear. We investigated the effects of probiotics on the efficacies of ICIs in patients treated with and without chemotherapy. We investigated patients with advanced NSCLC on ICI monotherapy or combination ICI and chemotherapy using the Okayama Lung Cancer Study Group Immunotherapy Database (OLCSG-ID) and the Okayama Lung Cancer Study Group Immunochemotherapy Database (OLCSG-ICD). In total, 927 patients (482 on ICI monotherapy, 445 on an ICI + chemotherapy) were enrolled. Most were male, of good performance status, smokers, and without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutations. Probiotics were administered to 19% of patients on ICI monotherapies and 17% of those on ICIs + chemotherapy. Of the former patients, progression-free survival (PFS) and overall survival (OS) were significantly better in the probiotics group (PFS 7.9 vs. 2.9 months, hazard ratio [HR] 0.54, p < .001; OS not attained vs. 13.1 months, HR 0.45, p < .001). Among patients receiving ICI and chemotherapy, there were no significant differences in PFS between those on probiotics and not but OS was significantly better in the probiotics group (PFS 8.8 vs. 8.6 months, HR 0.89, p = .43; OS not attained vs. 22.6 months, HR 0.61, p = .03). Patients on probiotics experienced better outcomes following ICI treatment.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Probiotics , Humans , Male , Female , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Databases, Factual , Probiotics/therapeutic use
2.
Transl Lung Cancer Res ; 12(10): 2098-2112, 2023 Oct 31.
Article in English | MEDLINE | ID: mdl-38025818

ABSTRACT

Background: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance. Methods: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC. Results: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation. Conclusions: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

3.
Cancer Sci ; 114(11): 4343-4354, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37715310

ABSTRACT

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Humans , Mice , Anaplastic Lymphoma Kinase/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Interleukin-15 , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/genetics
4.
Acta Med Okayama ; 77(2): 199-201, 2023 Apr.
Article in English | MEDLINE | ID: mdl-37094958

ABSTRACT

Meningitis-retention syndrome (MRS) is the combination of aseptic meningitis and acute urinary retention that occurs in the absence of other neurological diseases. The cause(s) of MRS remain unclear. A 57-year-old Japanese woman was referred to our hospital for the evaluation of persistent fever and headache. The fever's cause was initially unclear, but the presence of urinary retention raised concern about possible aseptic meningitis despite no physical indications of meningeal irritation. Only typical cases of MRS have been reported thus far to our knowledge, and it is important that clinicians are aware of MRS when it presents in this atypical form.


Subject(s)
Meningitis, Aseptic , Meningitis , Urinary Retention , Female , Humans , Middle Aged , Meningitis, Aseptic/complications , Meningitis, Aseptic/diagnosis , Urinary Retention/diagnosis , Urinary Retention/etiology , Syndrome , Hospitals
5.
J Cancer Res Clin Oncol ; 149(8): 4933-4938, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36308525

ABSTRACT

BACKGROUND: Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy (ICI + chemotherapy) has become the standard first line treatment for driver oncogene-negative advanced non-small-cell lung cancer (NSCLC). However, it may be more toxic compared to monotherapy, which limits its use. Moreover, the feasibility of the combination therapy in clinical practice remains unknown. METHODS: We conducted a cohort study to determine the implementation rate of ICI + chemotherapy in clinical practice. We retrospectively reviewed clinical data from advanced NSCLC patients who received systemic therapy at 13 institutions between December 2018 and December 2020. RESULTS: After excluding 154 patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene alterations, a total of 919 NSCLC patients were included. Among them, 442 were treated with ICI + chemotherapy (48%), whereas 477 were treated with other therapies (52%). Among these 477 patients, 340 did not receive ICI + chemotherapy because of intolerance (71%); thus, more than one-third of the advanced NSCLC patients do not benefit from the combination therapy due to intolerance. Among the 659 NSCLC patients for whom PD-L1 was < 50% or unknown, only 342 received the ICI + chemotherapy combination (52%) even though it is considered preferable to either therapy alone; the remaining 318 patients were treated with other therapies (48%). Among the 318 patients who did not receive ICI + chemotherapy, 274 were intolerant to it (86%). CONCLUSION: Our results revealed that a substantial proportion of advanced NSCLC patients did not benefit from ICI + chemotherapy due to intolerance. As treatments for NSCLC are moving toward combinations for greater efficacy, their feasibility in clinical practice must be taken into consideration.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Cohort Studies , Retrospective Studies , Oncogenes
6.
Cancers (Basel) ; 14(24)2022 Dec 14.
Article in English | MEDLINE | ID: mdl-36551668

ABSTRACT

Objectives: Combined immune checkpoint inhibitor (ICI) therapy and chemotherapy has become the standard treatment for advanced non-small-cell lung cancer (NSCLC). Pleural effusion (PE) is associated with poor outcomes among patients with NSCLC undergoing chemotherapy. However, minimal data exists on PE for patients undergoing combined ICI and chemotherapy. Therefore, we investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. Methods: We identified patients with advanced NSCLC undergoing chemotherapy and ICI therapy from the Okayama Lung Cancer Study Group−Immune Chemotherapy Database (OLCSG−ICD) between December 2018 and December 2020; the OLCSG−ICD includes the clinical data of patients with advanced NSCLC from 13 institutions. Then, we analyzed the treatment outcomes based on the presence of PE. Results: We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without PE (median PFS: 6.2 months versus 9.1 months; p < 0.001; median OS: 16.4 months versus 27.7 months; p < 0.001). The negative effect of PE differed based on the patient's programmed cell death-ligand 1 (PD-L1) expression status; with the effect being more evident in patients with high PD-L1 expression. In addition, PFS and OS did not differ between patients who did and did not undergo bevacizumab treatment; thus, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. Conclusion: PE is associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy.

7.
Cancer Immunol Res ; 10(9): 1111-1126, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35802887

ABSTRACT

Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in nonsmoking-related, non-small cell lung cancer (NSCLC). EGFR-mutant NSCLC has a noninflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune-checkpoint inhibitors, such as antiprogrammed cell death-1 (anti-PD-1), have weak antitumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by the sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, the simultaneous triple blockade had no such effect. The PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pretreatment with the EGFR-TKI, suggesting that the treatment schedule is crucial for the efficacy of the dual blockade therapy. Pretreatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing the expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a noninflamed TME.


Subject(s)
CD8-Positive T-Lymphocytes , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Protein Kinase Inhibitors , CD8-Positive T-Lymphocytes/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/immunology , ErbB Receptors , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Tumor Microenvironment , Vascular Endothelial Growth Factor Receptor-2/genetics
8.
J Reprod Immunol ; 152: 103659, 2022 08.
Article in English | MEDLINE | ID: mdl-35803114

ABSTRACT

There are a limited number of studies in which the depression status was followed up throughout pregnancy and postpartum to 1 year after delivery though 8.6-33% of women with recurrent pregnancy loss (RPL) and 10-25% of women who undergo in vitro fertilization and embryo transfer (IVF-ET) suffer from depression. We examined whether RPL and IVF-ET affect depressive symptoms during pregnancy and postpartum. A nationwide large-scale birth cohort study known as the "Japan Environment and Children's Study (JECS)" was conducted. The subjects consisted of 99,202 pregnant women recruited between January 2011 and March 2014. The Kessler Psychological Distress Scale was used for the 1st trimester, 2nd/3rd trimester and 1 year postpartum. The Edinburgh Postnatal Depression Scale was used for the first and the sixth month postpartum. The screening instruments were used to quantify depressive symptoms. Women with no live births had a significantly higher prevalence of elevated depressive symptoms throughout pregnancy and postpartum. The prevalence of elevated depressive symptoms was significantly higher in the second/third trimester among women with three or more pregnancy losses with no live births. IVF-ET was associated with reduced risk of developing depressive symptoms during all pregnancies and at 1 and 6 months after delivery in women with no live births. RPL and IVF-ET did not affect postpartum depressive symptoms, and IVF-ET rather reduced the risk of depression throughout pregnancy and postpartum. Psychological support for RPL women would be necessary.


Subject(s)
Abortion, Habitual , Infertility , Abortion, Habitual/epidemiology , Child , Cohort Studies , Depression/diagnosis , Depression/epidemiology , Depression/psychology , Female , Humans , Japan/epidemiology , Postpartum Period , Pregnancy
9.
Child Abuse Negl ; 127: 105581, 2022 05.
Article in English | MEDLINE | ID: mdl-35259689

ABSTRACT

BACKGROUND: Longitudinal adverse effects of neglect-related behaviors during postpartum, especially repeated maternal non-responsiveness to the crying baby on their neuropsychological developmental trajectory, have not been fully clarified. OBJECTIVE: This study aimed to examine the association between postpartum maternal neglect-related behaviors and infant neuropsychological outcomes using the Japan Environment and Children's Study (JECS). PARTICIPANTS AND SETTING: JECS data on 100,286 mother-child pairs were analyzed. Explanatory variables were "frequency of leaving the baby alone at home" (i.e., leaving the baby alone at home) and "frequency of ignoring the baby when he or she cries" (i.e., ignoring the crying baby) at one month postpartum. The outcomes were measured using the Japanese version of the Ages & Stages Questionnaires-Third Edition (J-ASQ-3). METHODS: After multiple imputations, logistic regression analysis was performed to evaluate the association between neglect-related behaviors and the J-ASQ-3 domains at each age. RESULTS: The "sometimes or more" group of "ignoring the crying baby" from six months to three years reported relatively consistent significant associations with developmental delay in communication (maximum adjusted odds ratio [aOR]: 1.456, 95% confidence interval [CI]: 1.261-1.682), gross motor (maximum aOR: 1.279, 95% CI: 1.159-1.411), fine motor (maximum aOR: 1.274, 95% CI: 1.113-1.457), problem-solving (maximum aOR: 1.178, 95% CI: 1.104-1.256), and personal-social domains (maximum aOR: 1.326, 95% CI: 1.255-1.402). The adverse effects of "leaving the baby alone at home" disappeared in many domains by the age of one. CONCLUSIONS: Repeated maternal non-responsiveness to baby's crying during postpartum may suppress multiple neuropsychological development during early childhood.


Subject(s)
Crying , Postpartum Period , Child, Preschool , Crying/psychology , Family , Female , Humans , Infant , Japan/epidemiology , Risk Factors
10.
Article in English | MEDLINE | ID: mdl-34769889

ABSTRACT

To discuss appropriate physical activity (PA) levels during pregnancy, this prospective cohort study examined the relationships between PA levels before and during pregnancy and physical and mental health status. Fixed data for 104,102 pregnant women were used from the Japan Environment and Children's Study, of which data for 82,919 women were analyzed after excluding women with multiple birth and pregnancy complications. PA levels were measured using the International Physical Activity Questionnaire-Short Form. The 8-Item Short Form Health Survey was used to measure outcomes. Logistic regression with multiple imputations showed that moderate PA for over 720 min/wk and vigorous PA before pregnancy were associated with poorer mental health in the first trimester (adjusted odds ratio (AOR): 1.087-1.376. Walking in the second and third trimesters was associated with better physical and mental health (AOR: 0.855-0.932). Moderate PA over 1080 min/wk and vigorous PA in the second and third trimesters were associated with poorer mental health (AOR: 1.223-1.873). Increases over 4135.4 MET-min/wk and decreases in PA levels were associated with poorer mental and physical health (AOR: 1.070-1.333). Namely, pregnant women receiving health benefits prefer continuous walking in addition to avoiding vigorous PA and excessive changes in PA levels during pregnancy.


Subject(s)
Exercise , Pregnant Women , Child , Female , Health Status , Humans , Japan/epidemiology , Pregnancy , Prospective Studies
11.
Mol Cancer Ther ; 20(9): 1653-1662, 2021 09.
Article in English | MEDLINE | ID: mdl-34158345

ABSTRACT

After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the EGFR and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. In this article, we report the potential role of Src homology 2 domain-containing phosphatase 2 (SHP2) in the residual cells of ALK/ROS1/EGFR-altered non-small cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells, whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC.


Subject(s)
Anaplastic Lymphoma Kinase/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Pyrimidines/pharmacology , Animals , Apoptosis , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Proliferation , Drug Synergism , Drug Therapy, Combination , ErbB Receptors/genetics , Female , Gene Expression Regulation, Neoplastic , Gene Rearrangement , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
12.
Thorac Cancer ; 12(8): 1248-1251, 2021 04.
Article in English | MEDLINE | ID: mdl-33651475

ABSTRACT

In non-small cell lung cancer (NSCLC), uncommon epidermal growth factor receptor (EGFR) mutations are mutations other than Ex19 deletion and Ex21 L858R, which are common mutations highly sensitive to EGFR-tyrosine kinase inhibitors. Afatinib, a second-generation EGFR-tyrosine kinase inhibitor, has been shown to be effective in patients with uncommon mutations. Dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, has not previously been shown to be effective in patients with uncommon mutations. Here, we report the efficacy of dacomitinib for uncommon EGFR mutations in a 71-year-old woman diagnosed with metastatic lung adenocarcinoma with uncommon EGFR mutation (Ex18 G719A). Afatinib was administered as the first-line treatment, and a remarkable antitumor effect was observed. However, the tumor grew after 14 months. Pemetrexed plus carboplatin followed by pemetrexed, docetaxel, atezolizumab and S-1 were performed in sequence. Although approximately four years had passed since the start of treatment, her physical condition was good. The patient started dacomitinib as the sixth-line treatment. Lesions were markedly reduced and treatment with dacomitinib was continued for 7.8 months. Dacomitinib is a possible treatment option for NSCLC with uncommon mutations.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Quinazolinones/therapeutic use , Aged , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/metabolism , Female , Humans , Lung Neoplasms/pathology , Mutation , Quinazolinones/pharmacology
13.
Cancer Sci ; 112(5): 1853-1864, 2021 May.
Article in English | MEDLINE | ID: mdl-33410241

ABSTRACT

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Molecular Targeted Therapy/methods , Neovascularization, Pathologic/prevention & control , Protein Kinase Inhibitors/therapeutic use , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , A549 Cells , Acrylamides/therapeutic use , Anaplastic Lymphoma Kinase/genetics , Aniline Compounds/therapeutic use , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Carbazoles/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Combined Modality Therapy/methods , Crizotinib/therapeutic use , Drug Synergism , Erlotinib Hydrochloride/therapeutic use , Female , Genes, erbB-1 , Heterografts , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Mutation , Oncogenes , Piperidines/therapeutic use , Platelet Endothelial Cell Adhesion Molecule-1/analysis , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Random Allocation , Signal Transduction/drug effects , Vascular Endothelial Growth Factor Receptor-2/metabolism , Ramucirumab
14.
Respir Investig ; 59(2): 240-246, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33436353

ABSTRACT

BACKGROUND: New therapeutic drugs have been developed for non-small cell lung cancer (NSCLC), and the prognosis of advanced NSCLC patients has improved. However, resistance to these drugs is a concern, and re-biopsy is necessary to determine the mechanism of drug resistance. There are many reports about the protocols for re-biopsy, including techniques such as bronchoscopy and computed tomography-guided needle biopsy (CTNB); however, there is no consensus on which method is optimal. Therefore, we retrospectively reviewed the bronchoscopy and CTNB re-biopsies conducted at our hospital. METHODS: We retrospectively analyzed 79 cases of re-biopsies with bronchoscopy or CTNB in patients with NSCLC from January 2014 to December 2016 at our institute. RESULTS: Forty-nine cases of bronchoscopy and 30 cases of CTNB were taken for re-biopsy. The diagnostic rates of bronchoscopy and CTNB were 83.7% and 100%, respectively (p = 0.023). The complication rates of bronchoscopy and CTNB were 18.4% and 36.7%, respectively (p = 0.11), with a statistically significant difference in the incidence of pneumothorax (0% vs. 23.3%, respectively; p < 0.01). Pneumothorax required drainage in 6.7% of all CTNB cases. There were no fatalities in either group. CONCLUSIONS: CTNB showed a higher diagnostic rate; however, it was associated with a higher rate of complications such as pneumothorax. Hence, the optimal modality must be determined individually for each patient.


Subject(s)
Biopsy, Needle/methods , Bronchoscopy/methods , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/pathology , Image-Guided Biopsy/methods , Lung Neoplasms/diagnosis , Lung Neoplasms/pathology , Tomography, X-Ray Computed/methods , Adult , Aged , Biopsy, Needle/adverse effects , Bronchoscopy/adverse effects , Female , Humans , Image-Guided Biopsy/adverse effects , Incidence , Male , Middle Aged , Pneumothorax/epidemiology , Pneumothorax/etiology , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Reoperation , Retrospective Studies
15.
Asia Pac J Clin Oncol ; 17(1): 101-108, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32885583

ABSTRACT

AIM: Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. METHODS: Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. RESULTS: The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. CONCLUSION: The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/adverse effects , Furosemide/therapeutic use , Kidney Diseases/prevention & control , Lung Neoplasms/drug therapy , Mannitol/therapeutic use , Adult , Aged , Drug Combinations , Female , Humans , Kidney Diseases/chemically induced , Male , Middle Aged
16.
Oncol Lett ; 20(6): 393, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33193853

ABSTRACT

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

17.
Biochem Biophys Res Commun ; 532(3): 341-346, 2020 11 12.
Article in English | MEDLINE | ID: mdl-32888648

ABSTRACT

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11-18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11-18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11-18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.


Subject(s)
Ado-Trastuzumab Emtansine/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Erlotinib Hydrochloride/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mutation , Protein Kinase Inhibitors/administration & dosage , Receptor, ErbB-2/genetics , Xenograft Model Antitumor Assays
18.
PLoS One ; 15(8): e0236935, 2020.
Article in English | MEDLINE | ID: mdl-32853277

ABSTRACT

BACKGROUND: Nintedanib is a multi-kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF); however, its efficacy and safety for patients with IPF and restricted pulmonary function remain unclear. Therefore, the objective of this study was to determine the efficacy and safety of nintedanib for patients with IPF and forced vital capacity (FVC) ≤ 50%. METHODS: This was a multi-center retrospective study performed by the Okayama Respiratory Disease Study Group. Patients were allocated into FVC ≤ 50% and FVC > 50% groups based on their predicted FVC. The primary endpoints were FVC changes from baseline after 6 and 12 months. RESULTS: 45 patients were eligible for the study. 18 patients had FVC ≤ 50%, and 27 patients had FVC > 50%. Overall, 31 and 19 patients underwent pulmonary function tests at 6 and 12 months after initiating nintedanib, respectively. FVC changes from baseline at 6 and 12 months after initiating nintedanib were comparable between the two groups. Adverse events were seen in all patients, and the rates of patients who discontinued nintedanib were also comparable (38.9% vs. 37.0%, p = 1.000). Multiple regression analysis showed that age and forced expiratory volume in 1 second (FEV1)/FVC were negatively correlated with changes in FVC at 6 months after initiating nintedanib. CONCLUSIONS: Our data suggest that nintedanib can be a useful agent for IPF patients, including those with a low FVC, and that age and FEV1/FVC are predictive markers for changes in FVC following nintedanib treatment.


Subject(s)
Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/physiopathology , Indoles/therapeutic use , Safety , Adult , Aged , Aged, 80 and over , Female , Humans , Indoles/adverse effects , Male , Middle Aged , Retrospective Studies , Vital Capacity
19.
Cancer Sci ; 111(10): 3739-3746, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32726470

ABSTRACT

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.


Subject(s)
B7-H1 Antigen/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/administration & dosage , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Male , Middle Aged , Progression-Free Survival
20.
Article in English | MEDLINE | ID: mdl-32604899

ABSTRACT

The effects of prenatal exposure to household pesticides on fetal and neonatal growth have not been fully clarified. The present study aims to determine the effects of prenatal exposure to pesticides on neonates' body size and growth during the first month. This study included 93,718 pairs of pregnant women and their children from the Japan Environment and Children's Study. Participants completed self-reporting questionnaires during their second or third trimesters on their demographic characteristics and frequency of pesticide use during pregnancy. Child weight, length, and sex were obtained from medical record transcripts. Birth weight and length, as well as weight and length changes over the first month, were estimated using an analysis of covariance. Frequency of exposure to almost all pesticides had no effects on birth weight and length. However, we found small but significant associations (i) between the use of fumigation insecticides and decreased birth weight, and (ii) between frequencies of exposure to pyrethroid pesticides, especially mosquito coils/mats, and suppression of neonatal length growth. Prenatal exposure to household pesticides, especially those containing pyrethroids, might adversely influence fetal and postnatal growth trajectories.


Subject(s)
Prenatal Exposure Delayed Effects , Adult , Birth Weight , Child , Female , Humans , Infant , Infant, Newborn , Japan , Male , Maternal Exposure/adverse effects , Pesticides/toxicity , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/epidemiology , Young Adult
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